Overexpression of p75NTR increases survival of breast cancer cells through p21waf1

The p75 neurotrophin receptor (p75NTR) plays a critical role in various neuronal and non-neuronal cell types by regulating cell survival, differentiation and proliferation. To evaluate the influence of p75NTR in breast cancer development, we have established and characterized breast cancer cells which stably overexpress p75NTR. We showed that p75NTR overexpression per se promoted cell survival to apoptogens with a concomitant slowdown of cell growth. The pro-survival effect is associated with an increased expression of the inhibitor of apoptosis protein-1 (c-IAP1), a decrease of TRAIL-induced cleavage of PARP, procaspase 9 and procaspase 3, and a decrease of cytochrome C release from the mitochondria. The anti-proliferative effect is due to a cell accumulation in G0/G1, associated with a decrease of Rb phosphorylation and an increase of p21waf1. Interestingly, inhibition of p21waf1 with siRNA not only restores proliferation but also abolishes the pro-survival effect of p75NTR, indicating the key role of p21waf1 in the biological functions of p75NTR. Finally, using a SCID mice xenograft model, we showed that p75NTR overexpression favors tumor growth and strongly increases tumor resistance to anti-tumoral treatment.Together, our findings suggest that p75NTR overexpression in breast tumor cells could favor tumor survival and contribute to tumor resistance to drugs. This provides a rationale to consider p75NTR as a potential target for the future design of innovative therapeutic strategies.